TY - JOUR
T1 - Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome
AU - Lockrow, Jason
AU - Boger, Heather
AU - Bimonte-Nelson, Heather
AU - Granholm, Ann Charlotte
N1 - Funding Information:
This work was supported by the Anna and John J. Sie Foundation for Down Syndrome and the National Institutes on Aging ( AG12122 ). We thank Dr. Narayan Bhat for valuable scientific discussions and Selena Sumner, Alfred Moore, and Claudia Umphlet for outstanding technical assistance. In addition, we would like to thank Dr. Louis Reichardt for the gift of TrkA antibodies.
PY - 2011/8/10
Y1 - 2011/8/10
N2 - Memantine is a partial NMDA receptor antagonist that has been shown to improve learning and memory in several animal models, and is approved for the treatment of Alzheimer's disease (AD). Chronic treatments using memantine in animal models of Alzheimer's disease show disease-modifying effects and suggest a potential neuroprotective function. The present study assessed the effects of both short- and long-term memantine treatment in a mouse model of Down syndrome (DS), the Ts65Dn mouse. The Ts65Dn mouse contains a partial trisomy of murine chromosome 16, and exhibits hippocampal-dependent memory deficits, as well as progressive degeneration of basal forebrain cholinergic neurons (BCFNs). Ts65Dn mice were treated with memantine for a period of 6 months, beginning at 4 months of age. At the end of treatment the mice underwent memory testing using novel object recognition and water radial arm maze tasks, and then histologically analyzed for markers of neurodegeneration. Memantine treatment improved spatial and recognition memory performance in the Ts65Dn mice, though not to the level of normosomic littermate controls. Despite these memory improvements, histological analysis found no morphological signs of neuroprotection of basal forebrain cholinergic or locus coeruleus neurons in memantine-treated Ts65Dn mice. However, memantine treatment of Ts65Dn mice gave rise to elevated brain-derived neurotrophic factor expression in the hippocampus and frontal cortex, suggesting a mechanism of behavioral modification. Thus, our findings provide further evidence for memory facilitation of memantine, but suggest pharmacological rather than neuroprotective effects of memantine both after acute and chronic treatment in this mouse model.
AB - Memantine is a partial NMDA receptor antagonist that has been shown to improve learning and memory in several animal models, and is approved for the treatment of Alzheimer's disease (AD). Chronic treatments using memantine in animal models of Alzheimer's disease show disease-modifying effects and suggest a potential neuroprotective function. The present study assessed the effects of both short- and long-term memantine treatment in a mouse model of Down syndrome (DS), the Ts65Dn mouse. The Ts65Dn mouse contains a partial trisomy of murine chromosome 16, and exhibits hippocampal-dependent memory deficits, as well as progressive degeneration of basal forebrain cholinergic neurons (BCFNs). Ts65Dn mice were treated with memantine for a period of 6 months, beginning at 4 months of age. At the end of treatment the mice underwent memory testing using novel object recognition and water radial arm maze tasks, and then histologically analyzed for markers of neurodegeneration. Memantine treatment improved spatial and recognition memory performance in the Ts65Dn mice, though not to the level of normosomic littermate controls. Despite these memory improvements, histological analysis found no morphological signs of neuroprotection of basal forebrain cholinergic or locus coeruleus neurons in memantine-treated Ts65Dn mice. However, memantine treatment of Ts65Dn mice gave rise to elevated brain-derived neurotrophic factor expression in the hippocampus and frontal cortex, suggesting a mechanism of behavioral modification. Thus, our findings provide further evidence for memory facilitation of memantine, but suggest pharmacological rather than neuroprotective effects of memantine both after acute and chronic treatment in this mouse model.
KW - Alzheimer's disease
KW - BDNF
KW - Brain derived growth factor
KW - Cholinergic neuron
KW - Hippocampus
KW - Inflammation
KW - Novel object recognition
KW - Radial arm maze
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U2 - 10.1016/j.bbr.2010.03.036
DO - 10.1016/j.bbr.2010.03.036
M3 - Article
C2 - 20363261
AN - SCOPUS:79955723158
SN - 0166-4328
VL - 221
SP - 610
EP - 622
JO - Behavioural Brain Research
JF - Behavioural Brain Research
IS - 2
ER -